Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues in collaboration with an international consortium. To further pursue a preliminary finding of linkage between melanoma and markers on 1p36 within a subset of our families, mutations and polymorphisms in a candidate gene, CDC2L1 were evaluated. One mutation was found in a melanoma cell line. Four polymorphisms in the promoter region were found among family members and within melanoma cell lines. We also evaluated melanocytic lesions among individuals with CDKN2A mutations, CDK4 mutations, and no identified mutations (in CDKN2A or CDK4). There were no substantive differences in the clinical or histologic features of melanomas or dysplastic nevi among these individuals. Overall, there was no apparent difference in the stage of prospective melanomas occuring in these families. Genetic analyses of Italian melanoma families continue. A pilot study is underway to assess the accrual of new Italian melanoma-prone families. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include two new families. Based on these families, multipoint analyses of affecteds only revealed a maximum LOD score of 4.78 at marker D7S500, with a 2-LOD support interval from marker D7S512 to marker D7S684. Attempts to identify the gene continue. Studying families with lymphoproliferative cancers has been a long-standing interest. We have described CLL kindreds, evaluated candidate genes (i.e. ATM), potential susceptibility markers (i.e. telomerase), anticipation (early onset of disease in familial cases) and a key prognostic factor in the familial setting (CD38 and Vh gene mutation status). Most recently we have conducted a linkage analysis on suitable CLL kindreds. We are hosting an international meeting to develop a consortium to study familial CLL. We plan to expand the linkage study in cooperation with other major groups. A new study of Waldenstrom's macroglobulinemia was also initiated and is currently in the field phase. The non-Hodgkin's lymphoma families have been reactivated, and the development of another new consortium is being contemplated.